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While metformin has demonstrated anti-fibrotic properties, the mechanism by which it regulates fibroblast activation, the primary effector cells in fibrosis, remains unclear in POF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The therapeutic effects of metformin were investigated in CTX-treated mice and further explored its interaction with macrophage-fibroblast crosstalk using an in vitro co-culture system.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>RNA sequencing revealed that metformin suppressed the MIF\/CD74 signaling pathway, which was significantly activated by CTX in ovarian tissues. In vitro, CTX increased the CD86+\/CD206\u2009+\u2009macrophage ratio via NF-\u03baB pathway activation, indicating altered macrophage polarization. Metformin or the MIF inhibitor ISO-1 reversed this polarization imbalance, thereby attenuating fibroblast activation and extracellular matrix (ECM) production in co-culture models. Additionally, CD74 knockdown in fibroblasts downregulated ECM-related genes and inhibited MAPK\/JNK signaling, whereas CD74 overexpression exacerbated the fibrotic responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings highlight a novel mechanism by which metformin alleviates CTX-induced ovarian fibrosis by targeting the MIF\/CD74 axis to reprogram macrophage-fibroblast communication, suggesting metformin as a protective adjuvant to improve ovarian health during chemotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-025-07294-5","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T15:00:04Z","timestamp":1762959604000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Metformin protects against cyclophosphamide-induced ovarian fibrosis by MIF\/CD74-mediated macrophage polarization"],"prefix":"10.1186","volume":"23","author":[{"given":"Ping","family":"Nie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhejun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingling","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gendie E.","family":"Lash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bihui","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3473-6553","authenticated-orcid":false,"given":"Ping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"issue":"1","key":"7294_CR1","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1186\/s13048-024-01434-z","volume":"17","author":"H Chen","year":"2024","unstructured":"Chen H, Nie P, Li J, Wu Y, Yao B, Yang Y, Lash GE, Li P. 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